The term "electrotransport" as used herein refers generally to the delivery of an agent (e.g., a drug) through a membrane, such as skin, mucous membrane, or nails. The drug delivery is at least partially induced or aided by the application of an electric potential. For example, a beneficial therapeutic agent may be introduced into the systemic circulation of an animal (e.g., a human) by electrotransport delivery through the skin.
The electrotransport process has been found to be useful in the transdermal administration of drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, and many other drugs. Perhaps the most common use of electrotransport is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically. The pilocarpine stimulates the production of sweat; the sweat is collected and analyzed for its chloride content to detect the presence of the disease.
Presently known electrotransport systems use at least two electrodes, positioned in intimate contact with some portion of the animal's body (e.g. the skin). A first electrode, called the active or donor electrode, delivers the therapeutic agent (e.g. a drug or a prodrug) into the body by electrotransport. The second electrode, called the counter or return electrode, closes an electrical circuit with the first electrode through the animal's body. A source of electrical energy, such as a battery, supplies electric current to the body through the electrodes. For example, if the therapeutic agent to be delivered into the body is positively charged (i.e., a cation), the anode will be the active electrode and the cathode will serve as the counter electrode to complete the circuit. If the therapeutic agent to be delivered is negatively charged (i.e., an anion), the cathode will be the donor electrode and the anode will be the counter electrode.
Alternatively, both the anode and cathode may be used to deliver drugs of opposite electrical charge into the body. In this situation, both electrodes are considered donor and counter electrodes. For example, the anode can simultaneously deliver a cationic therapeutic agent and act as a "counter" electrode to the cathode. Similarly, the cathode can simultaneously deliver an anionic therapeutic agent into the body and act as a "counter" electrode to the anode.
A widely used electrotransport process, electromigration (also called iontophoresis), involves the electrically induced transport of charged ions. Another type of electrotransport, electroosmosis, involves the electrically facilitated flow of a liquid solvent either from the donor electrode to the counter electrode or from the counter electrode to the donor electrode, under the influence of the applied electric field.
Still another type of electrotransport process, electroporation, involves the formation of transiently existing pores in a biological membrane by the application of high voltage pulses. A therapeutic agent can in part be delivered through the skin by passive diffusion by reason of the concentration difference between the concentration of the drug in the donor reservoir of the ETS and the concentration of the drug in the tissues of the animal's body. In any given electrotransport process, more than one of these processes may be occurring simultaneously to a certain extent.
Accordingly, the term "electrotransport", as used herein, should be given its broadest reasonable possible interpretation so that it includes the electrically induced or enhanced transport of at least one therapeutic agent, whether charged, uncharged, or a mixture thereof. Further, the terms load current and the current flowing through the skin are defined as the current flowing between the two electrodes.
Electrotransport systems generally require a reservoir or source of the agent, or a precursor of such agent, that is to be delivered into the body by electrotransport. Examples of such reservoirs or sources of, preferably ionized or ionizable, agents include a pouch as described in Jacobsen U.S. Pat. No. 4,250,878, or a pre-formed gel body as disclosed in Webster U.S. Pat. No. 4,383,529. Such reservoirs are electrically connected to the anode or the cathode of an ETS to provide a fixed or renewable source of one or more desired therapeutic species.
Recently, a number of U.S. Patents have issued in the electrotransport field, indicating a continuing interest in this mode of drug delivery. For example, Vernon et al U.S. Pat. No. 3,991,755, Jacobsen et al U.S. Pat. No. 4,141,359, Wilson U.S. Pat. No. 4,398,545, Jacobsen U.S. Pat. No. 4,250,878, Sorenson et al. U.S. Pat. No. 5,207,752, Lattin et al. U.S. Pat. No. 5,213,568, and Flower U.S. Pat. No. 5,498,235 disclose examples of electrotransport systems and some applications thereof. All of the above mentioned patents are hereby incorporated in their entirety by reference.
More recently, electrotransport delivery systems have become much smaller, particularly with the development of miniaturized electrical circuits (e.g., integrated circuits) and more powerful lightweight batteries (e.g., lithium batteries). The advent of inexpensive miniaturized electronic circuitry and compact, high-energy batteries has meant that the entire system can be made small enough to be unobtrusively worn on the skin of the patient and under clothing. This allows the patient to remain fully ambulatory and able to perform all normal activities, even during periods when the electrotransport system is actively delivering a drug.
However, some disadvantages still remain in the ETS prior art that restrict the wider application of ETS devices. One such disadvantage is the difficulty in regulating the rate of drug delivery to the user of the ETS when the apparent transport efficiency of the ETS for the drug in use is not constant. (The term "apparent transport efficiency", hereinafter "ATE", refers to a measurement of the amount of drug delivered for a unit time period by an "ETS". More specifically, the ATE of an ETS for a drug in use is equal to the amount of the drug delivered per unit time period divided by the average electrical current output over that time period by the ETS. Herein, the "average electrical current" is the average current flowing between two electrodes of the ETS.)
The ATE of an ETS for a drug may vary as a function of time or as function of other parameters, such as the pH level of the donor electrode, when maintenance of a constant drug delivery rate is required. For example, in the case of the fentanyl-on-demand ETS, it is normally necessary that all doses delivered to the user in any time period during the application period be equal, so that the patient gets the same relief after each dose. If the drug delivery rate is not properly regulated, then a serious overdose or underdose situation may result. However, under certain conditions, the ATE of fentanyl delivered by an ETS appears to vary substantially during delivery by the ETS, making problematic the delivery of fentanyl by a prior art ETS at a constant rate.
Stabilization of the ATE of some drugs to humans appears to occur rapidly, facilitating their delivery by prior art ETS technology. For example, several pilot clinical studies involving electrically assisted transdermal delivery of metoclopramide have repeatedly shown that the ATE for this drug appears to stabilize within an hour of application.
However, in certain applications, e.g., the demand delivery of fentanyl under certain conditions, the ATE of prior art ETS devices varies, preventing maintenance of the drug delivery rate within an acceptable range with prior art ETS devices.
Hence, there is a need for an improved ETS that maintains a constant drug delivery rate when the ATE varies.